Reformatsky reaction metals

The classical Reformatsky reaction consists of the treatment of an a-halo ester 1 with zinc metal and subsequent reaction with an aldehyde or ketone 3. Nowadays the name is used generally for reactions that involve insertion of a metal into a carbon-halogen bond and subsequent reaction with an electrophile. Formally the Reformatsky reaction is similar to the Grignard reaction. 

The complexation of achiral metal enolates by chiral additives, e.g., solvents or complexing agents could, in principle, lead to reagent-induced stereoselectivity. In an early investigation, the Reformatsky reaction of ethyl bromoacetate was performed in the presence of the bidentate ligand (—)-sparteine20. The enantioselectivity of this reaction varies over a wide range and depends on the carbonyl Compound, as shown with bcnzaldehyde and acetophenone. 

The Reformatsky reaction is a classical reaction in which metallic zinc, an a-haloester, and a carbonyl compound react to give a (i-hydroxyester.162 The zinc and a-haloester react to form an organozinc reagent. Because the carboxylate group can stabilize the carbanionic center, the product is essentially the zinc enolate of the dehalogenated ester.163 The enolate effects nucleophilic attack on the carbonyl group. 

Bieber reported that the reaction of bromoacetates is greatly enhanced by catalytic amounts of benzoyl peroxide or peracids and gives satisfactory yields with aromatic aldehydes. A radical chain mechanism, initiated by electron abstraction from the organometallic Reformatsky reagent, is proposed (Scheme 8.27).233 However, an alternative process of reacting aldehydes with 2,3-dichloro-l-propene and indium in water followed by ozonolysis provided the Reformatsky product in practical yields.234 An electrochemical Reformatsky reaction in an aqueous medium and in the absence of metal mediator has also been reported.235... 

This procedure is an adaptation of ones described by Dunna-vant and Hauser.2-4 Ethyl /3-hydroxy-/S,/3-diphenylpropionate has been prepared previously using the Reformatsky reaction by condensing ethyl a-bromoacetate with benzophenone by means of zinc metal.5... 

R3 R2 and R2 Ri gauche interactions however, for the same set of substituents, an increase in the steric requirements of either Rj or R3 will influence only one set of vicinal steric interactions (Rj R2 or R3 R2). Some support for these conclusions has been cited (eqs. [6] and [7]). These qualitative arguments may also be relevant to the observed populations of hydrogen- and nonhydrogen-bonded populations of the aldol adducts as well (see Table 1, entries K, L). Unfortunately, little detailed information exists on the solution geometries of these metal chelates. Furthermore, in many studies it is impossible to ascertain whether the aldol condensations between metal enolates and aldehydes were carried out under kinetic or thermodynamic conditions. Consequently, the importance of metal structure and enolate geometry in the definition of product stereochemistry remains ill defined. This is particularly true in the numerous studies reported on the Reformatsky reaction (20) and related variants (21). 

Several techniques have been used to activate the zinc metal and improve yields. For example, pretreatment of zinc dust with a solution of copper acetate gives a more reactive zinc-copper couple.130 Exposure to trimethylsilyl chloride also activates the zinc.131 Scheme 7.5 gives some examples of the Reformatsky reaction. 

Three approaches to zinc enolates are commonly adopted the process associated to the classical Reformatsky reaction is based on the insertion of Zn(0) into the carbon—halogen bond of an a-haloester. Two additional routes involve (i) transmetallation of a lithium enolate with a Zn(II) salt (Section V.A) and (ii) the transition-metal-catalysed conjugate addition of diethylzinc to Michael acceptors (Section V.B). 

The Reformatsky reactions are run following two basic procedures (i) a two-step Grignard-type protocol which first involves the formation of an organometallic zinc eno-late derivative followed by addition of the electrophile, and (ii) a Barbier-type protocol where the bromoester and the electrophile are simultaneously exposed to the action of zinc metal. 

An alternative strategy to improve the efficiency of Reformatsky reactions makes use of freshly prepared metal couples, particularly the Zn—Cu couple32 and the Zn—Ag couple33 in TFIF as solvent. 

The authors observed that the applied quantity of electricity (0.2-0.5 F) was always lower than the expected quantity on the basis of Zn consumed (1 g atom). This difference reflects the concurrence of two processes at the anode surface, where the electrochemically promoted reaction (Figure 4) coexists with a classic zinc metal-promoted Reformatsky reaction. Indeed, the electrochemical process produces at the working anode a perfectly clean zinc metal surface, very reactive towards the a-bromoester. 

Exotic metals of the sixth row have been also reported to promote Reformatsky reactions for example Rieke-barium74, which reacts efficiently with a-chloroketones, low-valent tantalum75 prepared from TaCL and Zn(0), and low-valent bismuth76 prepared from 3 and A1(0), which works in water as solvent. 

Generally carried out under basic conditions, often starting from the organozinc or organomagnesium derivative of an a-bromoester, the Reformatsky reaction. Equilibrium is shifted toward product by formation of a chelate structure with the metal ion. 

An enantioselective one-pot, three-component imino-Reformatsky reaction has been reported.20 Combining a benzaldehyde, an aniline, and an alkyl bromoacetate ester, (g) ees of up to 92% have been achieved in the /i-amino ester product, using a recyclable A-methylcphedrinc as auxiliary. A nickel(II) salt and dimethylzinc are employed the latter serves as dehydrating agent, reductant, and coordinating metal. 

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